210598orig1s000 - food and drug administration · reference id: 4320691 15 page(s) of draft...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

210598Orig1s000

OTHER REVIEW(S)

1

****Pre-decisional Agency Information**** Memorandum Date: September 14, 2018 To: Nina Ton, Pharm.D.

Regulatory Project Manager Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)

From: Taylor Burnett, Pharm.D.

Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) CC: Kathleen Klemm, Pharm.D., RAC

Team Leader OPDP

Subject: OPDP Labeling Comments for YUPELRI (revefenacin) inhalation solution,

for oral inhalation NDA: 210598

In response to DPARP’s consult request dated December 20, 2017, OPDP has reviewed the proposed product labeling (PI), Medication Guide, Instructions for Use (IFU), and carton and container labeling for the original NDA submission for YUPELRI (revefenacin) inhalation solution, for oral inhalation (Yupelri). OPDP’s comments on the proposed labeling are based on the draft PI received by electronic mail from DPARP on August 30, 2018, and are provided below. A combined OPDP and Division of Medical Policy Programs (DMPP) review was completed, and comments on the proposed Medication Guide, and IFU were sent under separate cover on September 14, 2018. OPDP has reviewed the attached proposed carton and container labeling submitted by the Sponsor to the electronic document room on November 10, 2017, and our comments are provided below. Thank you for your consult. If you have any questions, please contact Taylor Burnett at (240) 402-1349 or [email protected].

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion

Reference ID: 4320891

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TAYLOR B BURNETT09/14/2018

Signature Page 1 of 1


Department of Health and Human Services Public Health Service

Food and Drug Administration Center for Drug Evaluation and Research

Office of Medical Policy

PATIENT LABELING REVIEW

Date:

September 14, 2018

To:

Sally Seymour, MD Acting Director Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)

Through:

LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Sharon Williams, MSN, BSN, RN Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP)

From:

Nyedra W. Booker, PharmD, MPH Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Taylor Burnett, PharmD Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Subject: Review of Patient Labeling: Medication Guide (MG) and Instructions for Use (IFU)

Drug Name (established name):

YUPELRI (revefenacin)

Dosage Form and Route: inhalation solution, for oral inhalation Application Type/Number:

NDA 210598

Applicant: Theravance Biopharma US, Inc.


• ensured that the MG meets the Regulations as specified in 21 CFR 208.20

• ensured that the MG and IFU meet the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

4 CONCLUSIONS

The MG and IFU are acceptable with our recommended changes. 5 RECOMMENDATIONS

• Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence.

• Our collaborative review of the MG and IFU is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the MG and IFU.

Please let us know if you have any questions.




NYEDRA W BOOKER09/14/2018

TAYLOR B BURNETT09/14/2018

SHARON W WILLIAMS09/14/2018



1

MEMORANDUM REVIEW OF REVISED LABEL AND LABELING

Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM)

Office of Surveillance and Epidemiology (OSE)Center for Drug Evaluation and Research (CDER)

Date of This Memorandum: September 7, 2018

Requesting Office or Division: Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)

Application Type and Number: NDA 210598

Product Name and Strength: Yupelri (revefenacin) Inhalation Solution, 175 mcg/3 mL

Applicant/Sponsor Name: Theravance Biopharma Ireland Limited

FDA Received Date: September 5, 2018

OSE RCM #: 2017-2337-1

DMEPA Safety Evaluator: Lissa C. Owens, PharmD

DMEPA Team Leader: Sarah K. Vee, PharmD

1 PURPOSE OF MEMORANDUMDivision of Pulmonary, Allergy, and Rheumatology Products (DPARP) requested that we review the revised professional sample carton labeling for Yupelri (Appendix A) to determine if it is acceptable from a medication error perspective. The Applicant relocated the National Drug Code (NDC) and the ‘Rx Only’ statement to the opposite side of the principal display panel and revised the placeholder of ‘Tradename’ to ‘Yupelri’.

2 CONCLUSIONThe revised professional sample carton labeling for Yupelri is acceptable from a medication error perspective. We have no further recommendations at this time.


2

APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON SEPTEMBER 5, 2018Carton labeling


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LISSA C OWENS09/07/2018

SARAH K VEE09/07/2018



Surveillance inspection of covering

NDA 210598.

V. 1.1 Last Revised Date: 3-22-2018

After reviewing the inspectional findings, we conclude the analytical

data from Studies 0126, 0127 and 0135 (NDA 210598),

(not yet submitted) are reliable. Thus, the analytical data

from the current audited studies and other studies conducted by

using similar methods (Attachment 1) should be reliable for

review by the Agency without an inspection.

Inspected Studies

NDA 210598

Study #1: 0126

Study Title: “A Phase 3, 12-week, Randomized, Double−Blind,

Placebo−Controlled, Parallel Group Study of Nebulized

TD−4208 in Subjects with Chronic Obstructive Pulmonary

Disease”

Dates of Bioanalyses Conduct:

Study #2: 0127

Study Title: “A Phase 3, 12-week, Randomized, Double−Blind,

Placebo−Controlled, Parallel Group Study of Nebulized

TD−4208 in Subjects with Chronic Obstructive Pulmonary

Disease”


Study #3: 0135

Study Title: “The Effect of Severe Renal Impairment on the

Pharmacokinetics Following Single-Dose Inhaled

Administration of TD-4208”


Study not yet submitted to the Agency


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NDA 210598.


end of the current surveillance interval should be reliable for

review by the Agency without an inspection.

Zhou Chen, M.D., Ph.D.

Lead Pharmacologist

Yiyue Zhang, Ph.D.

Visiting Associate

Final Classification:

Analytical

NAI -

cc:

OTS/OSIS/Kassim/Choe/Kadavil/Fenty-Stewart/Nkah/CDER-OSIS-BEQ

OTS/OSIS/DNDBE/Bonapace/Dasgupta/Ayala/Biswas/Chen/Zhang

OTS/OSIS/DGDBE/Cho/Jang/Choi/Skelly/Au

Draft: YZ 8/3/2018, 8/7/2018

Edit: ZC 8/3/2018; RCA 8/3/2018; 8/7/2018; GB 8/8/2018

ECMS: Cabinets/CDER_OTS/Office of Study Integrity and

Surveillance/INSPECTIONS/BE Program/ANALYTICAL/

OSIS File#:

FACTS#:


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NDA 210598.


Attachment 1

Studies in Support of Pending Application

Application # Study # Study Type Drug Name Dates of conduct

NDA 210598

0126 In Vivo PK

Revefenacin 0127 In Vivo PK

0135 In Vivo PK


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YIYUE ZHANG08/09/2018

ZHOU CHEN08/09/2018

RUBEN C AYALA08/09/2018

GOPA BISWAS08/09/2018Gopa Biswas signing on behalf of Charles Bonapace.



Clinical Inspection Summary NDA 210598 Revefenacin

Protocol 0128

Protocol Title: A Phase 3, 52-week, Randomized, Active−Controlled Parallel Group Study to Evaluate the Safety and Tolerability of Nebulized TD−4208 in Subjects with Chronic ObstructivePulmonary Disease.

This was a randomized, active-controlled, parallel-group study in subjects with moderate tovery severe stable chronic obstructive pulmonary disease (COPD). Subjects were randomized to one of three treatment groups (revefenacin 88 mcg, revefenacin 175 mcg, or tiotropium 18 mcg) administered once daily in the morning for 52 weeks.

The primary objective of this study was to characterize the safety and tolerability of revefenacin administered once daily for 52 weeks in a population of patients with moderate to very severe COPD. The exploratory objectives were to evaluate the change from baseline forced expiratory volume at 1 second (FEV1) over 12 months, to evaluate concomitant use of rescue medications over 12 months, and to evaluate the effect of revefenacin on Health Outcomes assessments.

The primary safety and tolerability were evaluated by frequency and severity of adverse events, clinical laboratory measurements, physical examinations, ECGs (including Holter subset), vital signs, and vital status. For exploratory efficacy endpoints, FEV1 were measured by spirometer in the clinic at pre-dose and at 1, 3, 6, 9 and 12 months. The use of rescue medication (puffs per day) and days without any use of rescue medication were also analyzed. Health Outcomes Assessments included St. Georges Respiratory Questionnaire (SGRQ) (with a 1-month recall period), Modified Medical Research Council Dyspnea Scale (mMRC), COPD Assessment Tool (CAT), Clinical COPD Questionnaire (CCQ), Treatment Satisfaction Questionnaire, and Baseline and Transition Dyspnea Index (BDI/TDI).

The main inclusion criteria of the study included eligible male or female subjects with moderateto very severe COPD, 40 years of age or older, smoking history of at least 10 pack-years, a post-ipratropium FEV1/forced vital capacity (FVC) ratio < 0.7, and a post-ipratropium FEV1 of < 80% of predicted normal and > 700 mL.

The study randomized 1060 subjects and enrolled the first patient on September 21, 2015 and the last patient completed the last visit on May 24, 2017.

3. RESULTS (by site):

Name of CI, Address Site #, Protocol #, and # of Subjects

Inspection Date Classification

Lon D. Lynn, DO5115 N. Armenia AvenueTampa, FL 33603

Site 38823Protocol 0126Subjects: 24

February 12-16, 2018

NAI



In general, this clinical site appeared to be in compliance with Good Clinical Practices. Data submitted by this clinical site appear acceptable in support of this specific indication.

2. Edward E. Lisberg, M.D. (Site 38705, Protocol 0127, River Forest, IL)

The site screened 44 subjects and enrolled 30 subjects for Study Protocol 0127. Among the 30 enrolled subjects, 24 subjects completed the study and six subjects discontinued from the study. The reasons for discontinuations were due to withdrawal by subject (Subjects

and adverse events (COPD exacerbation for Subjects The discontinuation data listing provided in the NDA were verified by review of source documents. An audit of 24 of 30 enrolled subjects’ records was conducted.

The inspection evaluated the following documents: source records, screening and enrollment logs, eligibility criteria, case report forms, electronic files, study drug accountability logs, study monitoring visits, efficacy endpoints, adverse event reporting, and correspondence. Informed consent documents, IRB correspondence, and sponsor-generated correspondence were also inspected. Source documents for enrolled subjects whose records were reviewed were verified against the case report forms and NDA subject line listings. There were no limitations during conduct of the clinical site inspection.

Source documents for the raw data used to assess the primary study endpoint were verifiable at the study site. No under-reporting of adverse events was noted.

A Form FDA 483 was issued with the observations listed below at the end of inspection:

1) An investigation was not conducted in accordance with the investigational plan.Specifically,

Subject used an antibiotic for respiratory tract infection within 6 weeks of visit 1B and should have been excluded from the study.

Subject experienced a severe exacerbation of COPD on but was not discontinued from the study until

Other observations were discussed at the close of the inspection included the following:

Subject back dated the date of their signature on the Authorization to Use and Disclose Personal Health Information section of the informed consent document.

The site failed to obtain an annual update financial disclosure form from Noemi Mendoza, CCRC, Sub-investigator.

One whole blood sample and one PK sample for Subject was sent to the lab unlabeled.

One 30 minutes Post dose PK sample was not taken for Subject at visit 5. There was no documentation, for all subjects, of date/time when PK samples were stored

into the freezer or when they were removed for processing/shipping to the laboratory for analysis.


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Incomplete source data were noted- Subject relationship to drug blank on AE form- Subject inclusion criteria 3 and 4 blank on CRF- Subject visit 3 spirometry values blank in source

OSI Reviewer’s comments:The protocol deviations in Form 483 observations were reported in the NDA submission by the sponsor. These protocol deviations appear isolated and unlikely to have significant impact on the primary efficacy endpoint and safety results of the study. PK sampling procedure review was added to this inspection per DPARP clinical team request and the findings were shared with DPARP clinical review team and clinical pharmacology review team. Additional PK data inspections were requested by clinical pharmacology review team for this application and will be conducted by OSIS to verify PK data in the NDA submission.

In general, this clinical site appeared to be in compliance with Good Clinical Practices. Data submitted by this clinical site appear acceptable in support of efficacy and safety of this application.

3. Humberto Cruz, D.O. (Site 38713, Protocol 0128, Orlando, FL)

The site screened 54 subjects and enrolled 37 subjects for Study Protocol 0128. Among the 37 enrolled subjects, 26 subjects completed the study and 11 subjects discontinued from the study. The reasons for discontinuations were due to withdrawal by subject (Subjects

and adverse events (pulmonary embolism [Subject and fatal cardiac arrest [Subject The discontinuation data listing provided in the NDA were verified by review of source documents. An audit of 25 of 37 enrolled subjects’ records was conducted.

The inspection evaluated the following documents: source records, screening and enrollment logs, case report forms, study drug accountability logs, study monitoring visits, and correspondence. Informed consent documents, IRB documents and sponsor-generated correspondence were also inspected. Source documents for enrolled subjects whose records were reviewed were verified against the case report forms and NDA subject line listings. There were no limitations during conduct of the clinical site inspection.

Source documents for the raw data used to assess the primary study endpoint were verifiable at the study site. No under-reporting of adverse events was noted.

In general, this clinical site appeared to be in compliance with Good Clinical Practices. A Form FDA 483 (Inspectional Observations) was not issued. Data submitted by this clinical site appear acceptable in support of this specific indication.

{See appended electronic signature page}

Min Lu, M.D., M.P.H.


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Good Clinical Practice Assessment BranchDivision of Clinical Compliance EvaluationOffice of Scientific Investigations

CONCURRENCE:{See appended electronic signature page}

Janice Pohlman, M.D., M.P.H.Team Leader, Good Clinical Practice Assessment BranchDivision of Clinical Compliance EvaluationOffice of Scientific Investigations

CONCURRENCE:{See appended electronic signature page}

Kassa Ayalew, M.D.Branch Chief, Good Clinical Practice Assessment BranchDivision of Clinical Compliance EvaluationOffice of Scientific Investigations

cc: Central Doc. Rm. Review Division /Medical Team Leader/ Bob LimReview Division/Medical Officer/ Khalid PuthawalaReview Division /Project Manager/ Nina TonOSI/DCCE/ Division Director/Ni KhinOSI/DCCE/Branch Chief/Kassa AyalewOSI/DCCE/Team Leader/ Susan ThompsonOSI/DCCE/Team Leader/Janice Pohlman OSI/DCCE/GCP Reviewer/Min LuOSI/ GCP Program Analyst/Yolanda Patague


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MIN LU06/01/2018

KASSA AYALEW06/01/2018


1

LABEL AND LABELING REVIEWDivision of Medication Error Prevention and Analysis (DMEPA)

Office of Medication Error Prevention and Risk Management (OMEPRM)Office of Surveillance and Epidemiology (OSE)

Center for Drug Evaluation and Research (CDER)

*** This document contains proprietary information that cannot be released to the public***

Date of This Review: April 11, 2018

Requesting Office or Division: Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)

Application Type and Number: NDA 210598

Product Name and Strength: Revefenacin Inhalation Solution, 175 mcg/3 mL

Product Type: Single-Ingredient Combination Product

Rx or OTC: Rx

Applicant/Sponsor Name: Theravance Biopharma Ireland Limited

FDA Received Date: November 13, 2017

OSE RCM #: 2017-2337

DMEPA Safety Evaluator: Lissa C. Owens, PharmD

DMEPA Team Leader: Sarah K. Vee, PharmD


2

1 REASON FOR REVIEWThis review evaluates the proposed labels and labeling for Revefenacin Inhalation Solution for areas of vulnerability that could lead to medication errors. The Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) requested this review as part of their evaluation of NDA 210598.

2 MATERIALS REVIEWED

We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed.

Table 1. Materials Considered for this Label and Labeling Review

Material Reviewed Appendix Section (for Methods and Results)

Product Information/Prescribing Information A

Previous DMEPA Reviews B-N/A

Human Factors Study C-N/A

ISMP Newsletters D-N/A

FDA Adverse Event Reporting System (FAERS)* E-N/A

Other F-N/A

Labels and Labeling G

N/A=not applicable for this review*We do not typically search FAERS for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED

Theravance Biopharma Ireland Limited submitted a 505(b)(1) NDA 210598 on November 13, 2017, with the proposed indication of maintenance treatment of patients with chronic obstructive pulmonary disease (COPD),

DMEPA evaluated the proposed container labels, carton labeling, instructions for use, and prescribing information to determine whether there are any vulnerabilities that may lead to medication errors.

4 CONCLUSION AND RECOMMENDATIONS

We reviewed the proposed container labels, carton labeling, instructions for use, and prescribing information. We note that the label and labeling currently contain the placeholder ‘Tradename’ as the proposed proprietary name is currently under review. We make recommendations in section 4.1.


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4.1 RECOMMENDATIONS FOR THERAVANCE BIOPHARMA IRELAND LIMITED

We recommend the following be implemented prior to approval of this NDA:

A. Labels and Labeling1. We acknowledge that your proposed proprietary name is currently under review.

Replace the placeholder ‘Tradename’ once you have an approved proprietary name and submit the updated labels and labeling for review.


4

APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED

APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION

Table 2 presents relevant product information for Revefenacin received on November 13, 2017 from Theravance Biopharma Ireland Limited.

Table 2. Relevant Product Information for Revefenacin

Initial Approval Date N/A

Active Ingredient Revefenacin

Indication Maintenance treatment of patients with chronic obstructive pulmonary disease (COPD)

Route of Administration Oral Inhalation

Dosage Form Inhalation solution

Strength 175 mcg/3 mL

Dose and Frequency One 175 mcg vial (3 mL) once daily

How Supplied Sterile solution in low-density polyethylene vials. Each vial is overwrapped in a foil pouch and supplied in cartons containing 30 individually pouched unit-dose vials.

Storage Store at room temperature from 68°F to 77°F (20°C to 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C). Protect from direct sunlight and excessive heat.

Container Closure Paperboard shelf carton, each containing 30 individual aluminum foil laminate pouched LDPE vials


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APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling Reviewed

Using the principles of human factors and Failure Mode and Effects Analysis,a along with postmarket medication error data, we reviewed the following Revefenacin labels and labeling submitted by Theravance Biopharma Ireland Limited.

Foil Pouch received on November 13, 2017 LDPE embossed vial received on November 13, 2017 Carton labeling received on November 13, 2017 Professional Sample Foil Pouch received on November 13, 2017 Professional Sample Carton Labeling received on November 13, 2017 Instructions for Use (Image not shown) received on November 13, 2017 Medication Guide (Image not shown) received on November 13, 2017 Prescribing Information (Image not shown) received on November 13, 2017

G.2 Label and Labeling Images

a Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.



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LISSA C OWENS04/11/2018

SARAH K VEE04/11/2018


1

Interdisciplinary Review Team for QT Studies Consultation: Thorough QT Study Review

IND or NDA NDA 210598

Brand Name

Generic Name Revefenacin (TD-4208) Inhalation Solution

Sponsor Theravance Biopharma US Inc.

Indication Chronic Obstructive Pulmonary Disease

Dosage Form Inhaled nebulized dose

Drug Class Long-acting muscarinic receptor antagonist

Therapeutic Dosing Regimen 175 mcg once-daily

Duration of Therapeutic Use Chronic

Maximum Tolerated Dose 700 mcg once-daily

Submission Number and Date SDN 001; 10 Nov 2017

Review Division DPARP

Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document.

1 SUMMARY

1.1 OVERALL SUMMARY OF FINDINGS

No significant QTc prolongation effect of revefenacin (TD-4208) (175 mcg and 700 mcg) was detected in this TQT study. The largest upper bounds of the 2-sided 90% CI for the mean difference between revefenacin (175 mcg and 700 mcg) and placebo were below 10 ms, the threshold for regulatory concern as described in ICH E14 guidelines. The moxifloxacin profile over time is demonstrated in Figure 1. The largest lower bound of the two-sided 90% CI for the ΔΔQTcF for moxifloxacin was greater than 5 ms. The analytical results and the moxiflexicin profile adequately indicate that assay sensitivity was established.

In this randomized, blinded, four-period crossover study, 48 healthy subjects were randomized to receive revefenacin 175 mcg, revefenacin 700 mcg, placebo, and a single oral dose of moxifloxacin 400 mg. The point estimates and 90% CIs corresponding to the largest upper bounds for revefenacin (175 mcg and 700 mcg) and the largest lower bound for moxifloxacin is presented in Table 1.


2

Table 1: The Point Estimates and the 90% CIs Corresponding to the Largest Upper Bounds for Revefenacin (175 mcg and 700 mcg) and the Largest Lower Bound for

Moxifloxacin (FDA Analysis)

Treatment Time (hour) ΔΔQTcF (ms) 90% CI (ms)

Revefenacin 175 mcg 6 0.9 (-2.0, 3.8)

Revefenacin 700 mcg 8 0.8 (-1.3, 3.0)

Moxifloxacin 400 mg* 3 15.5 (13.9, 17.1)* Multiple endpoint adjustment was not applied. The largest lower bound after Bonferroni adjustment for 3 timepoints was 13.4 ms.

The supratherapeutic dose of revefenacin (700 mcg) produces approximately 4.1-fold and 4.9-fold the mean Cmax values of the mean Cmax for the therapeutic dose (175 mcg) of revefenacin and its major metabolite (THRX-195518), respectively. The supratherapeutic dose covers revefenacin and THRX-195518 exposures in the worst-case scenario of COPD patients with severe renal impairment or moderate hepatic impairment.

2 PROPOSED LABEL

The sponsor included the following QT-related language in their current proposed label.

12.2 Pharmacodynamics

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, double-blind, placebo- and positive-controlled, single dose, crossover trial in 48 healthy subjects. Following a single dose of revefenacin 700 mcg (4 times the recommended dosage), no effects on prolongation of QTc interval were observed.

The following is QT-IRT’s proposed labeling language, which is a suggestion only. We defer final labeling decisions to the Division.

12.2 PharmacodynamicsCardiac Electrophysiology

At a dose of 4 times the maximum approved recommended dose, revefenacin does not prolong the QT interval to any clinically relevant extent.

3 BACKGROUND

3.1 PRODUCT INFORMATION

Revefenacin (TD-4208) is a potent long-acting muscarinic receptor antagonist under development by Theravance Biopharma US Inc for the treatment of chronic obstructive pulmonary disease (COPD). Revefenacin is being developed as an inhalation solution for administration via standard jet nebulizer at a once daily dose of 175 mcg.

3.2 MARKET APPROVAL STATUS

Revefenacin is not approved for marketing in any country.


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3.3 PRECLINICAL INFORMATION

IC50 values for human hERG channel are 11.4 μM for revefenacin and 524 μM for its major metabolite, THRX-195518, which are >10,000-fold the Cmax values in subjects receiving 700 mcg of TD-4208. Increased HR was observed in dogs at inhaled doses of approximately 300 mcg/kg. At the no-effect dose level for increases in HR (100 mcg/kg), the Cmax in dogs is approximately 4-fold greater than clinical concentrations after a 700 mcg dose. No other treatment-related changes in ECG or cardiovascular parameters were observed in dogs at exposures (Cmax) up to 13-fold the clinical concentrations after a 700 mcg dose.

3.4 PREVIOUS CLINICAL EXPERIENCE

Revefenacin inhalation solution was evaluated in 3 single-dose studies in a total of 80 healthy adults, and in 7 repeat-dose studies in a total of 1,951 patients with COPD. Once daily repeat-doses ranging from 22 mcg to 700 mcg were well tolerated with no significant systemic anti-muscarinic activity. 88 mcg and 175 mcg once daily doses were evaluated in the Phase 3 study for a treatment duration of 52 weeks.

Atrial fibrillation was the most frequently reported cardiovascular treatment emergent adverse event (TEAE) in the phase 3 studies (pooled analysis of studies 0126, 0127 and 0128), with a 0.9% (n=7), 0.4% (n=3) and 0.5% (n= 2) incidence in the 88 mcg revefenacin, 175 mcg revefenacin and placebo group, respectively. Tachycardia was observed in 0.3% (n=2), 0.1% (n=1) and 0.2% (n=1) of the patients in the 88mcg revefenacin, 175 mcg revefenacin and placebo group, respectively. There were incidences of palpitations (88 mcg revefenacin: n=2, 175 mcg revefenacin: n=1) in the both the active groups. There were 3 incidences of ventricular extrasystoles in the 175 mcg group. QT-related TEAEs observed in the phase 2 studies are summarized in Appendix 6.1. (source: Summary of Clinical Safety-NDA210598)

3.5 CLINICAL PHARMACOLOGY

Appendix 6.1 summarizes the key features of revefenacin’s clinical pharmacology.

4 SPONSOR’S SUBMISSION

4.1 OVERVIEW

The QT-IRT reviewed the protocol prior to conducting this study under IND 119840 on 02/02/2016. The proposed TQT study was acceptable to FDA in the protocol review.

The sponsor submitted the study report 0136 for revefenacin, including electronic datasets and waveforms to the ECG warehouse.

4.2 TQT STUDY

4.2.1 TitleA Phase 1, Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Period Crossover Thorough QT Study to Evaluate the Effect of a Single Dose of TD-4208 on Cardiac Repolarization in Healthy Subjects


4

4.2.2 Protocol Number0136

4.2.3 Study Dates05 May 2016 - 29 Aug 2016

4.2.4 ObjectivesThe primary objective of this study was to:

Characterize the effect of a supratherapeutic (700 mcg) inhaled single dose of TD-4208 (hereafter referred to as revefenacin) on cardiac repolarization in healthy subjects.

The secondary objectives were to:

Characterize the effect of a therapeutic (175 mcg) inhaled single dose of revefenacin on cardiac repolarization in healthy subjects.

Evaluate the pharmacokinetics of revefenacin following therapeutic and supratherapeutic inhaled single doses of revefenacin in healthy subjects.

Evaluate the safety and tolerability following therapeutic and supratherapeutic inhaled single doses of revefenacin in healthy subjects.

Characterize the effect of therapeutic (175 mcg) and supratherapeutic (700 mcg) inhaled single doses of revefenacin on other electrocardiogram (ECG) parameters (heart rate [HR], PR, and QRS interval) in healthy subjects.

4.2.5 Study Description

4.2.5.1 DesignThis is a randomized, 4-sequence, crossover design with four dosing occasions. Each dosing occasion was followed by a washout period of at least 14 days.

4.2.5.2 ControlsThe sponsor used both placebo and positive (moxifloxacin) controls.

4.2.5.3 BlindingThe positive (moxifloxacin) control was not blinded. Other treatment arms were administered blinded using a double dummy approach.

4.2.6 Treatment Regimen

4.2.6.1 Treatment ArmsThere were 4 treatment arms:

Revefenacin 175 mcg (single dose, inhaled nebulized dose) Revefenacin 700 mcg (single dose, inhaled nebulized dose) Placebo (single dose, inhaled nebulized dose)


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Moxifloxacin 400 mg (single dose, oral tablet)

4.2.6.2 Sponsor’s Justification for DosesRevefenacin was generally well tolerated in a dose-ranging Phase 2b study that evaluated 44 mcg to 350 mcg once daily dosing for 28 days. 88 mcg was shown to be the minimally effective dose after 7 days of treatment. In a 7-day crossover study evaluating once-daily doses in the range of 22 mcg to 700 mcg, all doses were well tolerated and there was no indication of significant systemic antimuscarinic activity. In the 7-day study, all doses showed a sustained effect over 24 hours; the 700-mcg dose did not provide additional effect on lung function over the 350 mcg effect. A mechanistic study evaluating 175 mcg once daily and 44 mcg twice daily dosing regimens confirmed once-daily dosing as the appropriate dose frequency for revefenacin, with no advantage observed for the twice-daily regimen.

Reviewer’s Comment: Acceptable. The supratherapeutic dose (700 mcg) has a 4.1-fold and 4.9-fold higher mean Cmax values of revefenacin and THRX-195518, respectively, than that with the therapeutic dose (175mcg). Less than 1.6-fold accumulation in plasma was observed for both revefenacin and THRX-195518 upon once daily multiple-dose administration of inhalation solution. Metabolite: parent ratio for Cmax and AUC ranges from 1.5 to 3.8 and 3.5 to 6, respectively, in COPD patients. In healthy adults, mean Cmax and AUC of THRX-195518 were approximately 25-30% and 30-98% of revefenacin. The geometric mean Cmax of revefenacin and THRX-195518 is 1.06 and 1.79-fold higher, respectively, in individuals with severe renal impairment compared to those with normal renal function. Geometric mean Cmax of revefenacin and THRX-195518 is 1.02 and 1.49-fold higher, respectively, in moderate hepatic impairment compared to normal hepatic function. Overall, the supratherapeutic dose covers revefenacin and THRX-195518 exposures in the worst-case scenario of COPD patients with severe renal impairment or moderate hepatic impairment. (Source: 2.5 Clinical Overview, 2.7.2 Summary of Clinical Pharmacology studies)

4.2.6.3 Instructions with Regard to MealsStudy drugs were administered following an overnight fast of at least 10 hours (water was allowed during the fast). Administration of revefenacin or the placebo proceeded until nebulization of the study drug solution was complete, which was expected to take approximately 10 minutes and was evidenced by “spluttering” of the nebulizer. No food was administered within the 4 hours after the start of nebulization or after administration of the oral moxifloxacin tablet.

Reviewer’s Comment: Revefenacin is administered by inhalation route. Food is not expected to affect drug absorption.

4.2.6.4 ECG and PK AssessmentsPK: Blood samples for revefenacin, THRX-195518 and moxifloxacin PK assessment were collected pre-dose (within 30 minutes before dosing) and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.

ECG: On Day 1 of each study period, 25-hour continuous digital ECG monitoring was performed with replicate (minimum of 3) recordings at the following time points: -60, -


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45, and -30 minutes predose, 15 and 30 minutes, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose.

Reviewer’s Comment: The timing of ECG/PK sampling is acceptable as the Tmax for revefenacin and its major metabolite (~0.25 h to 0.5h) is covered and the timing also supports evaluation of potential delayed effects on the QTc interval.

4.2.6.5 BaselineThe average of 3 pre-dose QT/QTc values was used as baseline.

4.2.7 ECG CollectionIntensive 12-Lead Holter monitoring was used to obtain digital ECGs. Standard 12-Lead ECGs were obtained while subjects were recumbent.

4.2.8 Sponsor’s Results

4.2.8.1 Study SubjectsA total of 48 healthy subjects (29 females and 19 males) were enrolled in the study, 36 subjects (75%, 19 females and 17 males) completed all the study treatment periods. All 48 subjects were included in the safety, PK, and PD populations; 42 subjects were included in the PK/PD population.

The average age (SD) of the 48 subjects was 34.7 (9.7) years, ranging from 18.0 to 54.0 years. The majority of the subjects (46/48, 95.8%) were White. Thirty-nine subjects (39/48, 81.3%) were Hispanic or Latino, with the remaining 9 subjects (9/48, 18.8%) being Not Hispanic or Latino.

4.2.8.2 Statistical Analyses

4.2.8.2.1 Primary AnalysisFor primary analysis, the sponsor used linear mixed-effect model with terms sequence, period, time, treatment, sex, pre-dose baseline QTc, and treatment-by-time interaction. Subject nested within sequence was included as a random effect term.

Inhalation of 175-mcg and 700-mcg doses of revefenacin did not have an effect on the QTc interval. The ΔQTcF was similar after dosing with 175-mcg and 700-mcg revefenacin and placebo, and the resulting ΔΔQTcF was therefore small at all time points for revefenacin. The largest mean ΔΔQTcF after inhalation with 175-mcg revefenacin was 1.0 msec (95% CI: -1.2 to 3.1 msec) observed at 8 hours after dosing, and the largest mean ΔΔQTcF after the higher inhalation dose (700 mcg) reached 1.0 msec (95% CI: -1.1 to 3.1 msec) at 1 hour after dosing, with the upper bound of the 1-sided 95% CI excluding 10 msec.

The sponsor’s results for primary analysis are displayed in Table 2.


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Table 2: Least Squares Mean Estimate of Placebo-Corrected Change-From-Baseline QT Interval Corrected for Heart Rate Using Fridericia’s Formula (∆∆QTcF) by

Time (Primary Endpoint, Sponsor’s Results)

(Source: the sponsor’s clinical study report, Table 7, page 62)Reviewer’s Comments: The reviewer agrees with the sponsor’s conclusions. The statistical reviewer conducted independent analysis using repeated measures mixed-effect model without term sex. Instead of 95% CIs, 90% CIs for placebo-corrected mean change from baseline in QTcF were displayed. Results from the reviewer’s independent


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analysis are consistent with the sponsor’s. Please see the reviewer’s analysis in section 5.2.

4.2.8.2.2 Assay SensitivityThe sponsor’s results for assay sensitivity analysis are displayed in the above Table 2.

The QTc prolongation observed after dosing with moxifloxacin confirmed the study's assay sensitivity. Mean ΔΔQTcF was 10.8 msec, 11.9 msec, and 15.4 msec, respectively, at the 3 predefined time points (1, 2, and 3 hours after dosing) with the lower bound of the 95% CI above 5 msec (8.7 msec, 9.8 msec, and 13.3 msec, respectively).

Reviewer’s Comments: The reviewer agrees with the sponsor’s conclusions for assay sensitivity. Please see the reviewer’s independent analysis in section 5.2.

4.2.8.2.3 Categorical AnalysisFrom the sponsor’s report table for categorical analysis, there were no QTcF outliers in terms of QTcF >480 ms or ∆QTcF >60 ms. Only one subject (1/43, 2.3%) in the revefenacin 175 mcg group had QTcF between 450 ms and 480 ms. No subjects had ∆QTcF >30 ms in revefenacin 175 mcg group or revefenacin 700 mcg group.

4.2.8.3 Safety AnalysisNo deaths or serious adverse events (SAEs) occurred during the study. One subject (Subject was discontinued because of treatment emergent adverse events (TEAEs) during the study. The subject took a prohibited medication during the study and was recorded as a protocol deviation.

4.2.8.4 Clinical Pharmacology

4.2.8.4.1 Pharmacokinetic AnalysisThe PK results for revefenacin are presented in Table 3. Following administration of 700 mcg revefenacin the mean Cmax and AUC values in the thorough QT study were approximately 4.1 and 3.6-fold higher compared to the therapeutic dose. The mean Tmax was approximately 0.25 hours.

Table 3: Plasma Pharmacokinetic Parameters of Revefenacin following Administration a Single Dose by Inhalation

PK Parameter (unit) 175 mcg revefenacin

Arithmetic mean (SD)

700 mcg revefenacin

Arithmetic mean (SD)

Cmax (ng/mL) n= 43 0.345 (0.168) n= 45 1.42 (0.690)

Tmax (h) n= 43 0.25 (0.25, 0.33)

n= 45 0.25 (0.25, 0.28)

AUC0-24 (ng*h/mL) n= 40 0.284 (0.0998) n= 44 1.02 (0.433)

AUC0-last (ng*h/mL) n= 43 0.265 (0.119) n= 45 0.993 (0.454)


(b) (6)

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4.2.8.4.2 Exposure-Response AnalysisLinear mixed-effects modeling approach was used to explore the relationship between baseline-adjusted placebo- corrected QTc interval (ΔΔQTcF) and plasma concentrations of revefenacin. The estimated population slope of the exposure-response relationship was -0.298 msec per ng/mL (95% CI: -1.466 to 0.870) with an intercept of 0.319 msec. The slope of the relationship was not statistically significant and a concentration-dependent effect of revefenacin on QTcF was therefore not identified.

Reviewer’s Analysis: Reviewer’s analysis confirms the results of the sponsor (The estimated population slope of the exposure-response relationship was -0.35 msec per ng/mL (95% CI: -1.35 – 0.64) with an intercept of 0.3 msec). A plot of ΔΔQTcF vs. revefenacin concentrations is presented in Figure 3.

5 REVIEWERS’ ASSESSMENT

5.1 EVALUATION OF THE QT/RR CORRECTION METHOD

Since no large changes in heart rate were observed, i.e., mean changes ≤10 bpm (section 5.2.2), QTcF was used for primary analysis.

No assessment of the QT/RR correction methodology is necessary.

5.2 STATISTICAL ASSESSMENTS

5.2.1 QTc Analysis

5.2.1.1 The Primary Analysis for RevefenacinThe statistical reviewer used mixed model to analyze the QTcF effect. The model includes treatment, sequence, period, time point, and treatment by time point as fixed effects and subject as a random effect. Baseline values are also included in the model as a covariate. The analysis results are listed in the following tables.

Table 4: Analysis Results of QTcF and QTcF for Treatment Group = Revefenacin 175 mcg

ΔQTcF (ms)Revefenacin 175

mcg (N=43)

ΔQTcF (ms)Placebo (N=42)

ΔΔQTcF (ms)Revefenacin 175 mcg

Time(hour) LSmean LSmean LSmean 90% CI

0.25 -0.5 -0.6 0.1 (-1.4, 1.6)

0.5 -1.3 -2.0 0.7 (-0.7, 2.0)

1 -2.2 -1.9 -0.3 (-1.8, 1.3)

2 -0.2 -0.6 0.4 (-1.2, 1.9)

3 0.4 -0.2 0.6 (-1.0, 2.2)

4 1.2 0.9 0.3 (-1.4, 2.1)


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mcg (N=43)




6 -3.1 -4.0 0.9 (-2.0, 3.8)

8 -3.9 -4.8 0.9 (-1.3, 3.1)

12 -4.9 -3.6 -1.3 (-3.6, 1.0)

24 0.8 1.2 -0.4 (-2.2, 1.3)

Table 5: Analysis Results of QTcF and QTcF for Treatment Group = Revefenacin 700 mcg


mcg (N=45)




0.25 -0.5 -0.6 0.1 (-1.4, 1.6)

0.5 -1.0 -2.0 1.0 (-0.3, 2.3)

1 -0.8 -1.9 1.1 (-0.4, 2.7)

2 -0.1 -0.6 0.6 (-0.9, 2.1)

3 0.2 -0.2 0.4 (-1.2, 2.0)

4 1.4 0.9 0.5 (-1.2, 2.2)

6 -4.0 -4.0 -0.0 (-2.9, 2.9)

8 -3.9 -4.8 0.8 (-1.3, 3.0)

12 -3.4 -3.6 0.2 (-2.1, 2.4)

24 1.2 1.2 -0.0 (-1.7, 1.7)

The largest upper bounds of the 2-sided 90% CI for the mean differences between revefenacin 175 mcg and placebo, and between revefenacin 700 mcg and placebo were 3.8 ms and 3.0 ms, respectively.

5.2.1.2 Assay Sensitivity AnalysisThe statistical reviewer used the same statistical model to analyze moxifloxacin and placebo data. The results are presented in Table 6. The largest unadjusted 90% lower confidence interval was 13.9 ms. By considering Bonferroni multiple endpoint


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adjustment, the largest lower confidence interval was 13.4 ms, which indicates that an at least 5 ms QTcF effect due to moxifloxacin can be detected from the study.

Table 6: Analysis Results of QTcF and QTcF for Moxifloxacin

ΔQTcF (ms)Moxifloxacin

400 mg (N=44)


ΔΔQTcF (ms)Moxifloxacin 400 mg


Adjust90% CI*

0.25 -0.5 -0.6 0.1 (-1.4, 1.6) (-1.9, 2.0)

0.5 0.6 -2.0 2.6 (1.3, 4.0) (0.9, 4.4)

1 8.8 -1.9 10.7 (9.2, 12.3) (8.7, 12.8)

2 11.2 -0.6 11.9 (10.3, 13.4) (9.9, 13.9)

3 15.3 -0.2 15.5 (13.9, 17.1) (13.4, 17.6)

4 14.9 0.9 14.1 (12.3, 15.8) (11.8, 16.3)

6 6.5 -4.0 10.5 (7.6, 13.4) (6.8, 14.2)

8 7.0 -4.8 11.8 (9.6, 14.0) (9.0, 14.6)

12 6.4 -3.6 10.0 (7.7, 12.2) (7.0, 12.9)

24 7.0 1.2 5.8 (4.0, 7.5) (3.5, 8.1)

* Bonferroni method was applied to all time points to adjust for multiple endpoint evaluation at 3 time points around moxifloxacin Cmax.

5.2.1.3 Graph of QTcF Over TimeThe following figure displays the time profile of QTcF for different treatment groups.

(Note: CIs are all unadjusted including moxifloxacin)


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Figure 1: Mean and 90% CI QTcF Timecourse

5.2.1.4 Categorical AnalysisTable 7 lists the number of subjects as well as the number of observations whose QTcF values were ≤ 450 ms and between 450 ms and 480 ms. No subject’s QTcF was above 480 ms.

Table 7: Categorical Analysis for QTcF

Total N QTcF<=450 ms450<QTcF<=480

ms

TreatmentGroup

Subj. #

Obs. # Subj. # Obs. # Subj. # Obs. #

Baseline/Predose 48 522 46 (95.8%) 517 (99.0%) 2 (4.2%) 5 (1.0%)


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Total N QTcF<=450 ms450<QTcF<=480

ms

TreatmentGroup

Subj. #


Placebo 42 417 41 (97.6%) 415 (99.5%) 1 (2.4%) 2 (0.5%)

Moxifloxacin 400 mg 44 437 40 (90.9%) 432 (98.9%) 4 (9.1%) 5 (1.1%)

Revefenacin 175 mcg 43 430 42 (97.7%) 422 (98.1%) 1 (2.3%) 8 (1.9%)

Revefenacin 700 mcg 45 449 45 (100%) 449 (100%) 0 (0.0%) 0 (0.0%)

Table 8 lists the categorical analysis results for ΔQTcF. No subject’s change from baseline in QTcF was above 60 ms.

Table 8: Categorical Analysis of ΔQTcF

Total N ΔQTcF<=30 ms 30<ΔQTcF<=60 ms

TreatmentGroup

Subj. #


Placebo 42 417 42 (100%) 417 (100%) 0 (0.0%) 0 (0.0%)

Moxifloxacin 400 mg 44 437 42 (95.5%) 434 (99.3%) 2 (4.5%) 3 (0.7%)

Revefenacin 175 mcg 43 430 43 (100%) 430 (100%) 0 (0.0%) 0 (0.0%)

Revefenacin 700 mcg 45 449 45 (100%) 449 (100%) 0 (0.0%) 0 (0.0%)

5.2.2 HR AnalysisThe same statistical analysis was performed based on HR. The point estimates and the 90% confidence intervals are presented in Table 9. The largest upper limits of 90% CI for the HR mean differences between revefenacin 175 mcg and placebo and revefenacin 700 mcg and placebo were 1.9 bpm and 1.2 bpm, respectively.

The outlier analysis results for HR are presented in Table 10.

Table 9: Analysis Results of HR and HR

Revefenacin 175 mcg (N=43) Revefenacin 700 mcg (N=45)

ΔHR (bpm) ΔΔHR (bpm) ΔHR (bpm) ΔΔHR (bpm)

Time(hour) LSmean

LSmeanPlacebo LSmean (90% CI) LSmean

LSmeanPlacebo LSmean (90% CI)

0.25 2.7 2.8 -0.2 (-1.6, 1.2) 1.7 2.8 -1.1 (-2.5, 0.3)

0.5 1.4 0.9 0.5 (-0.7, 1.7) 0.3 0.9 -0.6 (-1.8, 0.6)

1 -0.0 0.1 -0.2 (-1.3, 1.0) -1.0 0.1 -1.1 (-2.3, -0.0)

2 -1.6 -1.1 -0.5 (-1.7, 0.7) -2.9 -1.1 -1.8 (-3.0, -0.6)


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ΔHR (bpm) ΔΔHR (bpm) ΔHR (bpm) ΔΔHR (bpm)

Time(hour) LSmean



3 -1.3 -0.7 -0.6 (-1.7, 0.6) -2.3 -0.7 -1.6 (-2.7, -0.5)

4 -0.6 -0.1 -0.5 (-1.8, 0.7) -1.3 -0.1 -1.2 (-2.5, 0.0)

6 5.6 6.6 -1.0 (-2.6, 0.6) 4.9 6.6 -1.7 (-3.3, -0.1)

8 3.6 3.3 0.3 (-1.2, 1.9) 3.1 3.3 -0.3 (-1.8, 1.2)

12 3.7 5.0 -1.3 (-2.8, 0.2) 3.2 5.0 -1.8 (-3.3, -0.3)

24 1.1 1.3 -0.2 (-1.7, 1.3) -0.1 1.3 -1.4 (-2.9, 0.1)

Table 10: Categorical Analysis for HR

Total N

HR<=100bpm

HR>100bpm

HR>45bpm

HR<=45bpm

TreatmentGroup Subj. # Subj. # Subj. # Subj. # Subj. #

Baseline/Predose 48 48 (100%) 0 (0.0%) 48 (100%) 0 (0.0%)

Placebo 42 42 (100%) 0 (0.0%) 41 (97.6%) 1 (2.4%)

Moxifloxacin 400 mg 44 44 (100%) 0 (0.0%) 44 (100%) 0 (0.0%)

Revefenacin 175 mcg 43 43 (100%) 0 (0.0%) 42 (97.7%) 1 (2.3%)

Revefenacin 700 mcg 45 45 (100%) 0 (0.0%) 44 (97.8%) 1 (2.2%)

5.2.3 PR AnalysisThe same statistical analysis was performed based on PR interval. The point estimates and the 90% confidence intervals are presented in Table 11. The largest upper limits of 90% CI for the PR mean differences between revefenacin 175 mcg and placebo and revefenacin 700 mcg and placebo were 3.2 ms and 3.3 ms, respectively.

There were no subjects who experienced PR interval greater than 200 ms in revefenacin 175 mcg group or revefenacin 700 mcg group.

Table 11: Analysis Results of PR and PR


ΔPR (ms) ΔΔPR (ms) ΔPR (ms) ΔΔPR (ms)

Time(hour) LSmean



0.25 -7.8 -8.1 0.3 (-1.4, 2.0) -7.0 -8.1 1.1 (-0.6, 2.8)


15


ΔPR (ms) ΔΔPR (ms) ΔPR (ms) ΔΔPR (ms)

Time(hour) LSmean



0.5 -4.2 -3.5 -0.7 (-2.5, 1.1) -3.2 -3.5 0.3 (-1.5, 2.1)

1 -4.4 -3.0 -1.4 (-3.3, 0.5) -2.7 -3.0 0.4 (-1.5, 2.2)

2 -3.6 -4.8 1.2 (-0.9, 3.2) -3.5 -4.8 1.3 (-0.7, 3.3)

3 -4.5 -3.5 -1.0 (-2.8, 0.9) -4.6 -3.5 -1.1 (-3.0, 0.7)

4 -5.2 -3.2 -2.0 (-3.7, -0.3) -6.0 -3.2 -2.8 (-4.4, -1.1)

6 -6.5 -7.0 0.5 (-1.4, 2.5) -9.3 -7.0 -2.2 (-4.2, -0.3)

8 -9.3 -9.0 -0.3 (-2.4, 1.8) -8.6 -9.0 0.4 (-1.7, 2.5)

12 -8.9 -7.7 -1.3 (-3.3, 0.8) -9.2 -7.7 -1.5 (-3.6, 0.5)

24 -4.1 -2.9 -1.2 (-3.2, 0.8) -2.8 -2.9 0.1 (-1.9, 2.1)

5.2.4 QRS AnalysisThe same statistical analysis was performed based on QRS interval. The point estimates and the 90% confidence intervals are presented in Table 12. The largest upper limits of 90% CI for the QRS mean differences between revefenacin 175 mcg and placebo and revefenacin 700 mcg and placebo were 0.7 ms and 0.9 ms, respectively.

The outlier analysis results for QRS are presented in Table 13.

Table 12: Analysis Results of QRS and QRS


ΔQRS (ms) ΔΔQRS (ms) ΔQRS (ms) ΔΔQRS (ms)

Time(hour) LSmean



0.25 -0.0 -0.1 0.1 (-0.2, 0.4) -0.2 -0.1 -0.1 (-0.4, 0.2)

0.5 0.2 0.2 -0.0 (-0.4, 0.3) 0.2 0.2 -0.0 (-0.3, 0.3)

1 0.0 -0.0 0.1 (-0.2, 0.3) 0.1 -0.0 0.2 (-0.1, 0.4)

2 -0.1 -0.2 0.1 (-0.2, 0.4) -0.1 -0.2 0.1 (-0.2, 0.4)

3 0.1 0.0 0.1 (-0.2, 0.4) -0.3 0.0 -0.3 (-0.5, 0.0)

4 0.2 -0.0 0.2 (-0.1, 0.6) 0.0 -0.0 0.1 (-0.3, 0.4)

6 -0.4 -0.5 0.1 (-0.5, 0.7) -0.6 -0.5 -0.1 (-0.7, 0.5)

8 -0.7 -0.6 -0.2 (-0.6, 0.2) -0.9 -0.6 -0.3 (-0.7, 0.1)


16


ΔQRS (ms) ΔΔQRS (ms) ΔQRS (ms) ΔΔQRS (ms)

Time(hour) LSmean



12 -0.8 -0.7 -0.1 (-0.7, 0.4) -0.4 -0.7 0.3 (-0.2, 0.9)

24 0.1 0.0 0.1 (-0.3, 0.4) 0.1 0.0 0.0 (-0.3, 0.4)

Table 13: Categorical Analysis for QRS

Total N QRS<=110 ms QRS>110 ms

TreatmentGroup Subj. # Obs. # Subj. # Obs. # Subj. # Obs. #

Baseline/Predose 48 522 40 (83.3%)

450 (86.2%)

8 (16.7%) 72 (13.8%)

Placebo 42 417 34 (81.0%)

357 (85.6%)

8 (19.0%) 60 (14.4%)

Moxifloxacin 400 mg 44 437 36 (81.8%)

378 (86.5%)

8 (18.2%) 59 (13.5%)

Revefenacin 175 mcg 43 430 37 (86.0%)

384 (89.3%)

6 (14.0%) 46 (10.7%)

Revefenacin 700 mcg 45 449 39 (86.7%)

393 (87.5%)

6 (13.3%) 56 (12.5%)

5.3 CLINICAL PHARMACOLOGY ASSESSMENTS

The mean revefenacin concentration-time profile is illustrated in Figure 2.


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Figure 2: Mean revefenacin concentration-time profiles for 175 mcg (black line) and 700 mcg (yellow line) dose

The relationship between ΔΔQTcF and revefenacin, the predominant moiety in plasma, is shown in Figure 3, which did not suggest an exposure-response relationship for QTcF consistent with the sponsor’s analysis.

Figure 3: ΔΔ QTcF vs. revefenacin concentration


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5.4 CLINICAL ASSESSMENTS

5.4.1 Safety assessmentsThere was 1 subject in the 700 mcg dose group who experienced syncope, which was considered mild in severity and possibly/probably related to study drug.

None of the other events identified to be of clinical importance per the ICH E14 guidelines (i.e. seizure, significant ventricular arrhythmias or sudden cardiac death) occurred in this study.

5.4.2 ECG assessmentsOverall ECG acquisition and interpretation in this study appears acceptable.

5.4.3 PR and QRS IntervalThere are no clinically meaningful effects on the PR and QRS intervals.


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6 APPENDIX

6.1 HIGHLIGHTS OF CLINICAL PHARMACOLOGY

(Source: QT-IRT review – IND 119840 -02/02/2016)

Note: Hepatic and renal impairment studies were on-going at the time of protocol review of the thorough QT-study (02/02/2016). The studies were completed in April, 2016 and May, 2016, respectively.


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---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

JANELL E CHEN03/27/2018

DALONG HUANG03/27/2018

MOHAMMAD A RAHMAN03/28/2018

SNEHAL N SAMANT03/28/2018

LARS JOHANNESEN03/28/2018

MICHAEL Y LI03/28/2018

CHRISTINE E GARNETT03/28/2018


210598orig1s000 - food and drug administration · reference id: 4320691 15 page(s) of draft...

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